EP1819686B1 - 5-hydroxy-benzothiazole derivatives having beta-2-adrenorecptor agonist activity - Google Patents

5-hydroxy-benzothiazole derivatives having beta-2-adrenorecptor agonist activity Download PDF

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EP1819686B1
EP1819686B1 EP05821742A EP05821742A EP1819686B1 EP 1819686 B1 EP1819686 B1 EP 1819686B1 EP 05821742 A EP05821742 A EP 05821742A EP 05821742 A EP05821742 A EP 05821742A EP 1819686 B1 EP1819686 B1 EP 1819686B1
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compound
formula
acid
compounds
tert
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EP1819686A1 (en
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Robin Alec Fairhurst
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Novartis AG
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Novartis AG
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Priority to SI200531406T priority patent/SI1819686T1/sl
Priority to EP10178492A priority patent/EP2305659A1/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62Benzothiazoles
    • C07D277/68Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/428Thiazoles condensed with carbocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/08Bronchodilators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to organic compounds, their preparation and use as pharmaceuticals.
  • WO 99/09018 discloses benzothiazolone derivatives having selective beta-2-receptor agonist activities.
  • WO 2004/016601 discloses benzothiazole derivatives having beta-2-adrenoreceptor agonist activity.
  • the invention provides in one aspect a compound of formula XI in free or salt or solvate form wherein T is as shown in the following table T
  • the compounds represented by formula XI are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts.
  • Pharmaceutically acceptable acid addition salts of the compound of formula I include those of inorganic acids, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid, para -biphenyl benzoic acid or triphenylacetic acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxy
  • the compounds represented by formula XI may exist in unsolvated or solvate forms.
  • Pharmaceutically acceptable solvates include hydrates and solvates wherein the solvent of crystallisation may be isotopically substituted, for example D 2 O, d 6 -acetone or d 6 -DMSO.
  • the compounds represented by formula XI include at least one asymmetric carbon atom and thus they exist in individual optically active isomeric forms or as mixtures thereof, e.g. as racemic or diastereomeric mixtures.
  • the present invention embraces individual optically active R and S isomers as well as mixtures, e.g. racemic or diastereomeric mixtures, thereof. These isomers may be separated by conventional techniques, e.g. by fractional crystallization or column chromatography.
  • the present invention also provides a process for the preparation of compounds of formula XI in free or salt or solvate form. They can be prepared by a process comprising:
  • Process variant A may be carried out using known procedures for reacting sulfonic acid esters with amines or analogously as hereinafter described in the Examples.
  • R c is preferably C 1 -C 4 -alkyl, but especially methyl.
  • the reaction is conveniently carried out in an organic solvent such as toluene.
  • the reaction temperature is conveniently from 0°C to 200°C, preferably from 70°C to 100°C, especially from 80°C to 90°C.
  • the temperature may be achieved by conventional heating or by microwave irradiation.
  • Process variant B may be carried out using known procedures for reacting epoxides with amines or analogously as hereinafter described in the Examples.
  • the reaction is conveniently carried out in an organic solvent such as toluene.
  • the reaction temperature is conveniently from 0°C to 200°C, preferably from 70°C to 100°C, especially from 80°C to 90°C.
  • the temperature may be achieved by conventional heating or by microwave irradiation.
  • R a and R b may be chosen in accordance with the nature of the functional group, for example as described in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, John Wiley & Sons Inc, Third Edition, 1999 , which reference also describes procedures suitable for replacement of the protecting groups by hydrogen.
  • R a is preferably C 1 -C 4 -alkyl, especially isopropyl.
  • R b is preferably C 1 -C 4 -alkyl, especially tert-butyl.
  • the protecting group may be introduced and removed using any conventional procedure.
  • a hydroxy group is protected by a benzyl group
  • the latter may be removed by catalytic hydrogenation in the presence of palladium on charcoal using conventional procedures, such as those used hereinafter in the Examples.
  • Compounds of formula XI in free form may be converted into salt form, and vice versa, in a conventional manner.
  • the compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallisation.
  • Compounds of formula XI can be recovered from reaction mixtures and purified in a conventional manner.
  • Isomers, such as enantiomers may be obtained in a conventional manner, e.g. by fractional crystallisation or asymmetric synthesis from correspondingly asymmetrically substituted, e.g. optically active, starting materials.
  • Compounds of formula II are novel and can be prepared by reacting a compound of formula IV where R a and R b are protecting groups, with a sulfonylchloride, for example methane sulphonyl chloride using known procedures for selective mono-sulphonylation reactions as described Zhou et al J. Organic Letters (2002), 4(1), pages 43-46 or analogously as hereinafter described in the Examples.
  • a sulfonylchloride for example methane sulphonyl chloride
  • reaction with (R)-1-(5- tert -Butoxy-2-isopropoxy-benzothiazol-7-yl)-ethane-1,2-diol gives the R-enantiomer whereas reaction with (S)-1-(5- tert -Butoxy-2-isopropoxy-benzothiazol-7-yl)-ethane-1,2-diol gives the S-enantiomer.
  • the reaction is conveniently carried out in an organic solvent such as pyridine.
  • the reaction temperature is conveniently from -20°C to 30°C, but preferably about 0°C.
  • Compounds of formula IIA are novel and may be prepared using known methods for preparing oxiranyl-substituted heterocyclic compounds, for example as described in international patent application WO 04/016601 .
  • compounds of formula IIA may prepared by heating compounds of formula II, e.g. between room temperature and 150° C, but preferably between 50 and 100° C, in the presence of a base in solvent such as toluene, tetrahydrofuran or dichloroethane.
  • Compounds of formula IIA may also be formed as intermediates during the aforementioned reaction of compounds of formula II with compounds of formula III to form compounds of formula XI.
  • Compounds of formula IV may be prepared by reacting a compound of formula V where R a and R b are protecting groups, with a dihydroxylating agent such as osmium tetroxide, either in the presence or absence a catalyst, for example (DHQD) 2 PHAL (1,4-bis(dihydroquinidinyl)phthalazine) and re-oxidant, for example K 3 Fe(CN) 6 , or with premixed dihydroxylating reagents such as AD-mix- ⁇ or AD-mix- ⁇ using known procedures for assymetrically dihydroxylating alkenes or analogously as hereinafter described in the Examples.
  • a dihydroxylating agent such as osmium tetroxide
  • a catalyst for example (DHQD) 2 PHAL (1,4-bis(dihydroquinidinyl)phthalazine)
  • re-oxidant for example K 3 Fe(CN) 6
  • the reaction is conveniently carried out in an organic solvent, for example tert-butanol/water, with osmium tetroxide, preferably in the presence of a catalyst such as (DHQD) 2 PHAL and with K 3 Fe(CN) 6 as the reoxidant.
  • the reaction temperature is conveniently from -10°C to 10°C, but preferably about 0°C.
  • Compounds of formula V may be prepared by olefination of a compound of formula VI where R a and R b is a protecting group, using known procedures for the reaction of aldehydes to form alkenes, for example the Wittig reaction, or analogously as hereinafter described in the Examples.
  • the reaction is conveniently carried out in an organic solvent, for example THF or DCM.
  • the reaction temperature is conveniently from 10°C to 40°C, but preferably room temperature.
  • Compounds of formula VI may be prepared by reacting a compound of formula VII where R a and R b are protecting groups and X is halo, preferably fluoro, with a strong base, for example tert.butyl lithium, and the intermediate anion quenched by the addition of an electrophile, for example dimethylformamide, using the procedure described by Stanetty et al J. Org. Chem. 1996, 61, 5130-5133 , or analogously as hereinafter described in the Examples.
  • the reaction is conveniently carried out in an organic solvent, for example THF.
  • the reaction temperature is conveniently over a range of -90°C to 20°C, but preferably between about -78°C to about -10°C.
  • Compounds of formula VII may be prepared by reacting a compound of formula VIII where R b is a protecting group and X is halo, with a compound of formula IX HO- R a IX where R a is a protecting group, using known procedures for reacting isothiocyantes with alcohols to form thiocarbamates or analogously as hereinafter described in the Examples.
  • R 1 is preferably C 1 -C 4 -alkyl, especially isopropyl.
  • the reaction is conveniently carried out preferably in the presence of a base, for example triethylamine.
  • the reaction temperature is conveniently from 0°C to 120°C, but preferably about 60°C.
  • Compounds of formula VIII may be prepared by known procedures for the conversion of anilines to isothiocyanates, for example by reacting a compound of formula X where R b is a protecting group and X is halo, with thiophosgene (thiocarbonyl dichloride) using known procedures for converting amines to isothiocyanates or analogously as hereinafter described in the Examples.
  • the reaction is conveniently carried out in an organic solvent such as chloroform, preferably in the present of a base, for example potassium carbonate.
  • the reaction temperature is conveniently from -20°C to 20°C, but preferably about 0°C.
  • compositions of formula XI in free, salt or solvate form are useful as pharmaceuticals. Accordingly the invention also provides a compound of formula XI in free, salt or solvate form for use as a pharmaceutical.
  • the compounds of formula XI in free, salt or solvate form hereinafter referred to alternatively as "agents of the invention", have good ⁇ 2 -adrenoreceptor agonist activity.
  • the ⁇ 2 agonist activity, onset of action and duration of action of the agents of the invention may be tested using the guinea pig tracheal strip in vitro assay according to the procedure of R.A. Coleman and A.T. Nials, J. Pharmacol. Methods 1989, 21, 71 .
  • the binding potency and selectivity for the ⁇ 2 -adrenoreceptor relative to the ⁇ 1 -adrenoreceptor can be measured by a classical filtration binding assay according to the procedure of Current Protocols in Pharmacology (S. J. Enna (editor-in-chief) et al, John Wiley & Son, Inc, 1998 ), or by cAMP determination in cells expressing ⁇ 2 - or ⁇ 1 - adreno-ceptor, according to the procedure of B. January et al, Brit. J. Pharmacol. 1998, 123, 701 .
  • the agents of the invention commonly have a rapid onset of action and have a prolonged stimulating action on the ⁇ 2 -adrenoreceptor, compounds of the Examples hereinbelow having K 1 ( ⁇ 2 ) values of the order of 0.1 to 1000 nM, having durations of action of the order of 1 to greater than 12 hours. Many of the compounds have binding selectivities for the ⁇ 2 -adrenoreceptor relative to the ⁇ 1 -adrenoreceptor from 1.5 to 500.
  • the compounds of Examples 2, 4, 9, 14 and 17 have ⁇ 2 binding potencies, measured by a classical filtration binding assay, represented by K i values of 0.061, 0.027, 0.016, 0.056 and 0.002 ⁇ M respectively.
  • the compounds of Examples 1 and 10 have T(50%) times (in minutes) of > 672 at 100 nM concentration, and 595 at 10 nM concentration respectively in the guinea-pig tracheal strip assay, where T(50%) is the time for inhibition of contraction to decay to 50% of its maximum value.
  • the agents of the invention are suitable for use in the treatment of any condition which is prevented or alleviated by activation of the ⁇ 2 -adrenoreceptor.
  • the agents of the invention are useful in the relaxation of bronchial smooth muscle and the relief of bronchoconstriction. Relief of bronchoconstriction can be measured in models such as the in vivo plethysmography models of Chong et al, J. Pharmacol. Toxicol. Methods 1998, 39, 163 , Hammelmann et al, Am. J. Respir. Crit. Care Med., 1997, 156, 766 and analogous models.
  • agents of the invention are therefore useful in the treatment of obstructive or inflammatory airways diseases.
  • agents of the invention commonly exhibit characteristics indicating a low incidence of side effects commonly encountered with ⁇ 2 agonists such as tachycardia, tremor and restlessness, such agents accordingly being suitable for use in on demand (rescue) treatment as well as prophylactic treatment of obstructive or inflammatory airways diseases.
  • Treatment of a disease in accordance with the invention may be symptomatic or prophylactic treatment.
  • Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "whezing symptoms and diagnosed or diagnosable as "whez infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "whez-infant syndrome".)
  • Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. corticosteroid) or bronchodilatory.
  • Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant from any previously administered symptomatic asthma therapy.
  • inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary or airways disease (COPD or COAD), including chronic bronchitis, or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy.
  • ARDS adult/acute respiratory distress syndrome
  • COAD or COAD chronic obstructive pulmonary or airways disease
  • chronic bronchitis or dyspnea associated therewith
  • emphysema emphysema
  • exacerbation of airways hyperreactivity consequent to other drug therapy in particular other inhaled drug therapy.
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis anthracosis
  • asbestosis chalicosis
  • ptilosis ptilosis
  • siderosis silicosis
  • tabacosis tabacosis and byssinosis.
  • the agents of the invention are also useful in the treatment of a condition requiring relaxation of smooth muscle of the uterus or vascular system. They are thus useful for the prevention or alleviation of premature labour pains in pregnancy. They are also useful in the treatment of chronic and acute urticaria, psoriasis, allergic conjunctivitis, actinitis, hay fever, and mastocytosis.
  • the agents of the invention are also useful as co-therapeutic agents for use in combination with other drug substances such as anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • An agent of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
  • the invention includes a combination of an agent of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said agent of the invention and said drug substance being in the same or different pharmaceutical composition.
  • Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in WO 02/88167 , WO 02/12266 , WO 02/100879 , WO 02/00679 (especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/35668 , WO 03/48181 , WO 03/62259 , WO 03/64445 , WO 03/72592 , WO 04/39827 and WO 04/66920 ; non-steroidal glucocorticoid receptor agonists, such as those described in DE 10261874 , WO 00/00531 , WO 02/10143 , WO 03/82280 , WO 03/82787 , WO 03/862
  • Suitable bronchodilatory drugs include anticholinergic or antimuscarinic agents, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in EP 424021 , US 3714357 , US 5171744 , WO 01/04118 , WO 02/00652 , WO 02/51841 , WO 02/53564 , WO 03/00840 , WO 03/33495 , WO 03/53966 , WO 03/87094 , WO 04/018422 and WO 04/05285 .
  • anticholinergic or antimuscarinic agents in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in EP 424021 , US 3714357 , US 5171744 , WO 01/04
  • Suitable dual acting bronchodilatory drugs include dual beta-2 adrenoceptor agonist / muscarinic antagonists such as those disclosed in US 2004/0167167 , WO 04/74246 and WO 04/74812 .
  • Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine as well as those disclosed in JP 2004107299 , WO 03/099807 and WO 04/026841 .
  • the agents of the invention are also useful as co-therapeutic agents for use in combination other beta-2 adrenoceptor agonists, for example as a rescue medication.
  • Suitable beta-2 adrenoceptor agonists include albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, carmoterol, procaterol, and especially, formoterol and pharmaceutically acceptable salts thereof, and compounds (in free or salt or solvate form) of formula I of WO 0075114 , preferably compounds of the Examples thereof, especially a compound of formula and pharmaceutically acceptable salts thereof, as well as compounds (in free or salt or solvate form) of formula I of WO 04/16601 , and also compounds of EP 1440966 , JP 05025045 , WO 93/18007 , WO 99/64035 , US 2002/0055651 , WO 01/42193 , WO 01/83462 , WO or
  • agents of the invention with anti-inflammatory drugs are those with antagonists of chemokine receptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, Takeda antagonists such as N-[[4-[[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-amin-ium chloride (TAK-770), and CCR-5 antagonists described in US 6166037 (particularly claims 18 and 19), WO 00/66558 (particularly claim 8), WO 00
  • Combinations of agents of the invention and steroids, PDE4 inhibitors, A 2A agonists, A 2B agonists or LTD4 antagonists may be used, for example, in the treatment of COPD or, particularly, asthma.
  • Combinations of agents of the invention and anticholinergic or antimuscarinic agents, PDE4 inhibitors, A 2A agonists, A 2B agonists, dopamine receptor agonists or LTB4 antagonists may be used, for example, in the treatment of asthma or, particularly, COPD.
  • the present invention also provided compounds of formula XI for use in a method for the treatment of an obstructive or inflammatory airways disease which comprises administering to a subject, particularly a human subject, in need thereof a compound of formula XI, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore described.
  • the invention provides a compound of formula XI, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore described for use in the preparation of a medicament for the treatment of an obstructive or inflammatory airways disease.
  • the agents of the invention may be administered by any appropriate route, e.g. orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; topically to the skin, for example in the treatment of psoriasis; intranasally, for example in the treatment of hay fever; or, preferably, by inhalation, particularly in the treatment of obstructive or inflammatory airways diseases.
  • any appropriate route e.g. orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; topically to the skin, for example in the treatment of psoriasis; intranasally, for example in the treatment of hay fever; or, preferably, by inhalation, particularly in the treatment of obstructive or inflammatory airways diseases.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula XI in free form or in the form of a pharmaceutically acceptable salt or solvate thereof, optionally together with a pharmaceutically acceptable diluent or carrier therefor.
  • Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art.
  • oral dosage forms may include tablets and capsules.
  • Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g. patches.
  • Compositions for inhalation may comprise aerosol or other atomizable formulations or dry powder formulations.
  • the composition comprises an aerosol formulation
  • it preferably contains, for example, a hydro-fluoro-alkane (HFA) propellant such as HFA134a or HFA227 or a mixture of these, and may contain one or more co-solvents known in the art such as ethanol (up to 20% by weight), and/or one or more surfactants such as oleic acid or sorbitan trioleate, and/or one or more bulking agents such as lactose.
  • HFA hydro-fluoro-alkane
  • the composition comprises a dry powder formulation, it preferably contains, for example, the compound of formula XI having a particle diameter up to 10 microns, optionally together with a diluent or carrier, such as lactose, of the desired particle size distribution and a compound that helps to protect against product performance deterioration due to moisture, such as magnesium stearate, e.g. 0.01 to 1.5%.
  • a diluent or carrier such as lactose
  • a compound that helps to protect against product performance deterioration due to moisture such as magnesium stearate, e.g. 0.01 to 1.5%.
  • the composition comprises a nebulised formulation, it preferably contains, for example, the compound of formula XI either dissolved, or suspended, in a vehicle containing water, a co-solvent such as ethanol or propylene glycol and a stabiliser, which may be a surfactant.
  • the invention also includes (A) a compound of formula XI as hereinbefore described in free form, or a pharmaceutically acceptable salt or solvate thereof, in inhalable form; (B) an inhalable medicament comprising such a compound in inhalable form together with a pharmaceutically acceptable carrier in inhalable form; (C) a pharmaceutical product comprising such a compound in inhalable form in association with an inhalation device; and (D) an inhalation device containing such a compound in inhalable form.
  • Dosages employed in practising the invention will of course vary depending, for example, on the particular condition to be treated, the effect desired and the mode of administration. In general, suitable daily dosages for administration by inhalation are of the order of from 1 to 5000 ⁇ g.
  • DCM dichloromethane
  • DMF dimethylformamide
  • DMSO dimethylsulphoxide
  • THF tetrahydrofuran
  • tert -Butanol (28.2g) is dissolved in dimethyl acetamide (200 ml). NaH (15.6 g, 60% dispersion in oil) is added over 15 minutes. The reaction mixture is stirred at room temperature for 2 hours. 3,5-diflourobromobenzene (50 g) is added drop wise over 30 minutes. The reaction mixture is stirred at room temperature until shown to be complete by HPLC. The reaction mixture is quenched by addition of water (10 ml), washed with water (1x), dried over MgSO 4 , filtered and the solvent removed in vacuo to give the title compound. 1 H nmr (CDCl 3 , 400 MHz); 7.00 (ddd, 1H), 6.95 (dd, 1H), 6.68 (ddd, 1H), 1.4 (s, 9H).
  • Ph 3 PMe.Br (5.0 g) is dissolved in dry tetrahydrofuran (100 ml) under argon. N-butyl lithium (8.8 ml, of 1.6 M solution) is added at room temperature over 10 minutes and reaction mixture stirred for a further 30 minutes. A solution of 5- tert -Butoxy-2-isopropoxy-benzothiazole-7-carbaldehyde (1.25 g) in dichloromethane (40 ml) is added drop wise to the reaction mixture and the reaction mixture is stirred for 4.5 hours at room temperature.
  • K 3 Fe(CN) 6 (1.2 g), K 2 CO 3 (0.5 g), (DHQD) 2 PHAL (19 mg) are dissolved in tert-butanol/water (15 ml, 1:1 mix) under argon and stirred for 15 minutes.
  • the reaction mixture is cooled to 0°C and OsO 4 (3.1 mg) is added followed by 5-tert-Butoxy-2-isopropoxy-7-vinyl-benzothiazole (0.35 g).
  • the reaction mixture is stirred over night at room temperature.
  • the reaction mixture is quenched with sodium-meta-bisulphate (1 g) and stirred for 1.5 hours.
  • This compound is prepared following the procedures described in international patent application WO 96/23760 .
  • This compound is prepared following the procedure described in international patent application WO 03/76387 .
  • Methanesulfonic acid ( R )-2-(5-tert-butoxy-2-isopropoxy-benzothiazol-7-yl)-2-hydroxy-ethyl ester (122 mg) and phentermine (165 mg) are dissolved in toluene (2 ml). The reaction mixture is heated to 90°C for 20 hours.

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EP05821742A 2004-11-29 2005-11-28 5-hydroxy-benzothiazole derivatives having beta-2-adrenorecptor agonist activity Not-in-force EP1819686B1 (en)

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PL05821742T PL1819686T3 (pl) 2004-11-29 2005-11-28 Pochodne 5-hydroksy-benzotiazolu o aktywności agonistów beta-2-adrenoreceptora
SI200531406T SI1819686T1 (sl) 2004-11-29 2005-11-28 5-hidroksi-benzotiazolni derivati z beta 2-adrenoreceptorsko agonistično aktivnostjo
EP10178492A EP2305659A1 (en) 2004-11-29 2005-11-28 5-hydroxy-benzothiazole derivatives having beta-2-adrenoreceptor agonist activity
CY20111101070T CY1112237T1 (el) 2004-11-29 2011-11-07 Παραγωγα 5-υδροξυ-βενζοθειαζολης που εχουν ενεργοτητα αγωνιστη βητα-2-αδρενοϋποδοχεα

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CY1112237T1 (el) 2015-12-09
US20080096940A1 (en) 2008-04-24
PT1819686E (pt) 2011-10-11
JP4648950B2 (ja) 2011-03-09
GB0426164D0 (en) 2004-12-29
EP2305659A1 (en) 2011-04-06
US8076489B2 (en) 2011-12-13
KR20070067733A (ko) 2007-06-28
CN101065370B (zh) 2012-11-14
WO2006056471A1 (en) 2006-06-01
JP2008520618A (ja) 2008-06-19
ATE520676T1 (de) 2011-09-15
US20120041041A1 (en) 2012-02-16
AU2005308909B2 (en) 2009-08-27
DK1819686T3 (da) 2011-12-05
ES2370833T3 (es) 2011-12-23
RU2007124329A (ru) 2009-01-10
BRPI0517894A (pt) 2008-10-21
CA2586443A1 (en) 2006-06-01
CA2586443C (en) 2014-09-02
SI1819686T1 (sl) 2011-12-30
AU2005308909A1 (en) 2006-06-01
EP1819686A1 (en) 2007-08-22
KR100891415B1 (ko) 2009-04-02
AU2005308909C1 (en) 2014-11-27
MX2007006374A (es) 2007-06-20
CN101065370A (zh) 2007-10-31
RU2402540C2 (ru) 2010-10-27

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